A Fetal Fatty-Acid Oxidation Disorder as a Cause of Liver Disease in Pregnant Women

Abstract Three patients presented with evidence of a fatty acid oxidation disorder. Analysis of urinary organic acids by gas chromatography/mass spectrometry demonstrated the presence of medium-chain (C6-C12) dicarboxylic, 3-hydroxydicarboxylic, and 3-ketodicarboxylic acids in all three urines. 3-Ketodicarboxylic aciduria is reported for the first time here, as are the mass spectra for 3-ketosuberic, 3-ketosebacic, and 3-ketododecanedioic acids and the oximated spectrum for 3-ketoadipic acid. The presence of 3-ketodicarboxylic acids suggests a defect at the level of a long-chain 3-ketoacyl-CoA thiolase, an enzyme for which a deficiency state has not previously been described. Our patients may represent the first cases of a long-chain thiolase defect.

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Effect of heat stress and bezafibrate on mitochondrial β-oxidation: Comparison between cultured cells from normal and mitochondrial fatty acid oxidation disorder children using in vitro probe acylcarnitine profiling assay

Brain and Development ◽

10.1016/j.braindev.2009.06.001 ◽

2010 ◽

Vol 32 (5) ◽

pp. 362-370 ◽

Cited By ~ 15

Author(s):

Hong Li ◽

Seiji Fukuda ◽

Yuki Hasegawa ◽

Hironori Kobayashi ◽

Jamiyan Purevsuren ◽

...

Keyword(s):

Heat Stress ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Cultured Cells ◽

Acid Oxidation ◽

Fatty Acid Oxidation Disorder ◽

Mitochondrial Fatty Acid Oxidation ◽

Mitochondrial Fatty Acid

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Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

Molecular and Cellular Biology ◽

10.1128/mcb.00227-16 ◽

2016 ◽

Vol 36 (20) ◽

pp. 2553-2567 ◽

Cited By ~ 24

Author(s):

Liang Guo ◽

Shui-Rong Zhou ◽

Xiang-Bo Wei ◽

Yuan Liu ◽

Xin-Xia Chang ◽

...

Keyword(s):

Fatty Acid ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Acid Oxidation ◽

Fatty Liver Disease ◽

Acid Oxidation ◽

Α Subunit ◽

Nonalcoholic Fatty Liver ◽

Mitochondrial Trifunctional Protein

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein α-subunit (MTPα) functions as a critical enzyme for fatty acid β-oxidation, but whether dysregulation of MTPα is pathogenically connected to NAFLD is poorly understood. We show that MTPα is acetylated at lysine residues 350, 383, and 406 (MTPα-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTPα-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTPα. Replacement of MTPα-3K with either MTPα-3KR or MTPα-3KQ inhibits cellular lipid accumulation both in free fatty acid (FFA)-treated alpha mouse liver 12 (AML12) cells and primary hepatocytes and in the livers of high-fat/high-sucrose (HF/HS) diet-fed mice. Moreover, knockdown of SIRT4 could phenocopy the effects of MTPα-3K mutant expression in mouse livers, and MTPα-3K mutants more efficiently attenuate SIRT4-mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTPα and MTPα-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTPα regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD.

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